Indications that paraoxonase-1 contributes to plasma high density lipoprotein levels in familial hypercholesterolemia

Abstract

HDL-associated paraoxonase type 1 (PON1) can protect LDL and HDL against oxidative modification in vitro and therefore may protect against cardiovascular disease. We investigated the effects of PON1 levels, activity, and genetic variation on high density lipoprotein-cholesterol (HDL-C) levels, circulating oxidized LDL (OxLDL), subclinical inflammation [high-sensitive C-reactive protein (Hs-CRP)], and carotid atherosclerosis. PON1 genotypes (L55M, Q192R, −107C/T, −162A/G, −824G/A, and −907G/C) were determined in 302 patients with familial hypercholesterolemia. PON1 activity was monitored by the hydrolysis rate of paraoxon, diazoxon, and phenyl acetate. PON1 levels, OxLDL, and Hs-CRP were determined using an immunoassay. The genetic variants of PON1 that were associated with high levels and activity of the enzyme were associated with higher HDL-C levels (P values for trend: 0.008, 0.020, 0.042, and 0.037 for L55M, Q192R, −107C/T, and −907G/C, respectively). In addition to the PON1 genotype, there was also a positive correlation between PON1 levels and activity and HDL-C (PON1 levels: r = 0.37, P < 0.001; paraoxonase activity: r = 0.23, P = 0.01; diazoxonase activity: r = 0.29, P < 0.001; arylesterase activity: r = 0.19, P = 0.03).Our observations support the hypothesis that both PON1 levels and activity preserve HDL-C in plasma. HDL-associated paraoxonase type 1 (PON1) can protect LDL and HDL against oxidative modification in vitro and therefore may protect against cardiovascular disease. We investigated the effects of PON1 levels, activity, and genetic variation on high density lipoprotein-cholesterol (HDL-C) levels, circulating oxidized LDL (OxLDL), subclinical inflammation [high-sensitive C-reactive protein (Hs-CRP)], and carotid atherosclerosis. PON1 genotypes (L55M, Q192R, −107C/T, −162A/G, −824G/A, and −907G/C) were determined in 302 patients with familial hypercholesterolemia. PON1 activity was monitored by the hydrolysis rate of paraoxon, diazoxon, and phenyl acetate. PON1 levels, OxLDL, and Hs-CRP were determined using an immunoassay. The genetic variants of PON1 that were associated with high levels and activity of the enzyme were associated with higher HDL-C levels (P values for trend: 0.008, 0.020, 0.042, and 0.037 for L55M, Q192R, −107C/T, and −907G/C, respectively). In addition to the PON1 genotype, there was also a positive correlation between PON1 levels and activity and HDL-C (PON1 levels: r = 0.37, P < 0.001; paraoxonase activity: r = 0.23, P = 0.01; diazoxonase activity: r = 0.29, P < 0.001; arylesterase activity: r = 0.19, P = 0.03). Our observations support the hypothesis that both PON1 levels and activity preserve HDL-C in plasma. Serum paraoxonase type 1 (PON1) is a HDL-associated enzyme capable of hydrolyzing lipid peroxides in LDL (1Mackness M.I. Arrol S. Durrington P.N. Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein.FEBS Lett. 1991; 286: 152-154Crossref PubMed Scopus (791) Google Scholar). Because oxidized low density lipoprotein (OxLDL) has atherogenic and proinflammatory properties (2Mertens A. Holvoet P. Oxidized LDL and HDL: antagonists in atherothrombosis.FASEB J. 2001; 15: 2073-2084Crossref PubMed Scopus (349) Google Scholar), PON1 may protect against atherosclerosis. This hypothesis is supported by observations in PON1-deficient mice, which are more prone to develop atherosclerosis than wild-type mice when fed a high-fat/high-cholesterol diet (3Shih D.M. Gu L. Xia Y.R. Navab M. Li W.F. Hama S. Castellani L.W. Furlong C.E. Costa L.G. Fogelman A.M. Lusis A.J.J. Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis.Nature. 1998; 394: 284-287Crossref PubMed Scopus (952) Google Scholar). An additional antiatherogenic property of PON1 is the inhibition of the oxidative modification of HDL and hence the preservation of HDL function (4Aviram M. Rosenblat M. Bisgaier C.L. Newton R.S. Primo-Parmo S.L. La Du B.N.N. Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase.J. Clin. Invest. 1998; 101: 1581-1590Crossref PubMed Scopus (1023) Google Scholar). HDL protects against cardiovascular disease (CVD) by means of reverse cholesterol transport (5Miller G.J. Miller N.E. Plasma-high-density-lipoprotein concentration and development of ischaemic heart-disease.Lancet. 1975; 1: 16-19Abstract PubMed Scopus (1975) Google Scholar). Even though the physiological role of PON1 in vivo remains to be clarified, the inhibition of both LDL and HDL oxidation may contribute to protection against CVD. PON1 expression is partly controlled by its molecular variation at the gene locus (6Simpson N.E. Serum arylesterase levels of activity in twins and their parents.Am. J. Hum. Genet. 1971; 23: 375-382PubMed Google Scholar). Two polymorphic sites have been described in the coding region: a leucine (L)-to-methionine (M) transition at position 55 (L55M) and a glutamine (Q)-to-arginine (R) transition at position 192 (Q192R). The L55M polymorphism affects the enzyme concentration, whereas the Q192R polymorphism affects the catalytic efficiency, but not the concentration (7Garin M.C. James R.W. Dussoix P. Blanche H. Passa P. Froguel P. Ruiz J.J. Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes.J. Clin. Invest. 1997; 99: 62-66Crossref PubMed Google Scholar, 8Humbert R. Adler D.A. Disteche C.M. Hassett C. Omiecinski C.J. Furlong C.E.E. The molecular basis of the human serum paraoxonase activity polymorphism.Nat. Genet. 1993; 3: 73-76Crossref PubMed Scopus (760) Google Scholar). Four polymorphisms in the promoter sequence of the PON1 gene (−107C/T, −162A/G, −824G/A, −907G/C) also contribute to the variability in protein expression. During an earlier study, our group found a relation between the PON1 genotype combination LLQQ and increased intima-media thickness (IMT), a surrogate marker of CVD, in high-risk subjects with familial hypercholesterolemia (FH) (9Leus F.R. Wittekoek M.E. Prins J. Kastelein J.J. Voorbij H.A.A. Paraoxonase gene polymorphisms are associated with carotid arterial wall thickness in subjects with familial hypercholesterolemia.Atherosclerosis. 2000; 149: 371-377Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). However, there is no consensus on the contribution of these genetic variants to the risk of CVD (10Wheeler J.G. Keavney B.D. Watkins H. Collins R. Danesh J. Four paraoxonase gene polymorphisms in 11212 cases of coronary heart disease and 12786 controls: meta-analysis of 43 studies.Lancet. 2004; 363: 689-695Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar). In addition to genetic influences, PON1 levels and activity could be modified by lifestyle determinants such as smoking (11James R.W. Leviev I. Righetti A. Smoking is associated with reduced serum paraoxonase activity and concentration in patients with coronary artery disease.Circulation. 2000; 101: 2252-2257Crossref PubMed Scopus (208) Google Scholar, 12Nishio E. Watanabe Y. Cigarette smoke extract inhibits plasma paraoxonase activity by modification of the enzyme's free thiols.Biochem. Biophys. Res. Commun. 1997; 236: 289-293Crossref PubMed Scopus (166) Google Scholar), vitamin C and E consumption (13Jarvik G.P. Tsai N.T. McKinstry L.A. Wani R. Brophy V.H. Richter R.J. Schellenberg G.D. Heagerty P.J. Hatsukami T.S. Furlong C.E.E. Vitamin C and E intake is associated with increased paraoxonase activity.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1329-1333Crossref PubMed Scopus (176) Google Scholar), and alcohol intake (14van der Gaag M.S. Tol A. van Scheek L.M. James R.W. Urgert R. Schaafsma G. Hendriks H.F.F. Daily moderate alcohol consumption increases serum paraoxonase activity: a diet-controlled, randomised intervention study in middle-aged men.Atherosclerosis. 1999; 147: 405-410Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar). Therefore, studying PON1 levels and activity, in conjunction with variation at the gene level, gives a more complete view of the role of PON1 in the development of atherosclerosis. The beneficial effects of PON1 on the inhibition of atherosclerosis might be more pronounced in a population that is prone to develop atherosclerosis than the general population. For this reason, we studied the role of PON1 in patients with FH. These patients are characterized by substantially increased serum low density lipoprotein-cholesterol (LDL-C) concentrations and sharply increased CVD risk. Our aim was to investigate the influence of PON1 genotypes and PON1 levels and activity on high density lipoprotein-cholesterol (HDL-C) levels, circulating OxLDL, inflammation markers [high-sensitive C-reactive protein (Hs-CRP)], and common carotid artery intima-media thickness (CCA-IMT) in patients with FH. The study population consisted of 325 men and women with FH who participated in a prospective, randomized, double-blind, two-center trial as described elsewhere (15Smilde T.J. Wissen S. Van Wollersheim H. Trip M.D. Kastelein J.J. Stalenhoef A.F.F. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial.Lancet. 2001; 357: 577-581Abstract Full Text Full Text PDF PubMed Scopus (873) Google Scholar). Of the 325 participants, 23 were excluded because there was no DNA available for PON1 genotyping. After an 8 week placebo run-in (in which all lipid-lowering drugs were discontinued), baseline height, weight, blood pressure, and CCA-IMT were measured. DNA, plasma, and serum samples were stored at −80°C until analysis. Studies have shown that PON1 levels and activity can only be measured correctly in serum samples (16Mackness B. Hunt R. Durrington P.N. Mackness M.I. Increased immunolocalization of paraoxonase, clusterin, and apolipoprotein A-I in the human artery wall with the progression of atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1233-1238Crossref PubMed Scopus (179) Google Scholar, 17Blatter Garin M.C. Abbott C. Messmer S. Mackness M. Durrington P. Pometta D. James R.W.W. Quantification of human serum paraoxonase by enzyme-linked immunoassay: population differences in protein concentrations.Biochem. J. 1994; 304: 549-554Crossref PubMed Scopus (116) Google Scholar). Because only one trial center collected additional serum for the determination of PON1 levels and activity, these measurements could be performed for only 134 of the 302 participants. All participants gave written informed consent, and the ethics committees of both trial centers approved the study. Total cholesterol, LDL-C, and were as described T.J. Trip M.D. Wollersheim H. Wissen S. Van Kastelein Stalenhoef and baseline of a trial the effects of conventional cholesterol lowering and thickness in patients with familial the versus on Invest. 2000; PubMed Scopus Google Scholar). of the common carotid was performed using a with a as described in elsewhere T.J. Wollersheim H. H. van Stalenhoef of measurements of carotid and artery in subjects and in patients with increased intima-media 1997; PubMed Scopus Google Scholar). The was measured in both the and of the of both were using a A complete of measurements was available for participants. The CCA-IMT was as the of both the and of the and The L55M and Q192R were determined by means of the by polymorphism using and as described by R. Adler D.A. Disteche C.M. Hassett C. Omiecinski C.J. Furlong C.E.E. The molecular basis of the human serum paraoxonase activity polymorphism.Nat. Genet. 1993; 3: 73-76Crossref PubMed Scopus (760) Google Scholar). DNA were on a and with The to the of a the to a and a the to a and the to a and a A was for (L55M) and DNA by with was to the promoter polymorphisms −107C/T, −162A/G, −824G/A, and for the of a coding for the polymorphisms at and were and for the of a coding for the polymorphisms at and were and The for polymorphisms and and for polymorphisms and were in and DNA The were and with the The for the and polymorphisms were as and For and we the as described by Leviev and James I. James R.W. polymorphisms of human paraoxonase PON1 gene and serum paraoxonase and Thromb. Vasc. Biol. 2000; PubMed Scopus Google Scholar). All of the were at by at and an PON1 levels were determined at the of and using an This has been described in elsewhere M. E. S. Miller N.E. A enzyme-linked for human serum paraoxonase Res. 2000; Full Text Full Text PDF PubMed Google Scholar). PON1 levels were measured in serum The and of variation were and Paraoxonase and diazoxonase were at the for and of the for and the The using and as in a and R.J. Furlong C.E. of paraoxonase (PON1) more than 1999; PubMed Scopus Google Scholar). After the addition of the serum for paraoxonase and for diazoxonase the was monitored on a for at Paraoxonase and diazoxonase are as of 1 1 of activity was measured at the of the of The as the rate of hydrolysis of phenyl This can be C.M. La Du The human serum J. Hum. Genet. Google Scholar). Serum samples were in of and in a of serum was to of 1 phenyl and The was monitored on a at in a at The hydrolysis of phenyl on the hydrolysis rate in the of was the rate of The to the rate of hydrolysis was A was for the of is as of 1 1 of phenyl We determined the concentrations of in samples that been with and at −80°C and not patients these We a available The and of variation were and Hs-CRP was measured by enzyme to the the The of variation was The between PON1 genotype, PON1 levels, PON1 activity, HDL-C levels, OxLDL, and CCA-IMT were in a in which PON1 genotype as the and the PON1 levels, PON1 activity, HDL-C levels, OxLDL, and CCA-IMT as the The influence of and on this was investigated in a analysis. The correlation was to the between the in and Hs-CRP a the in the and were on All of the were performed using levels with to PON1 levels and levels activity activity activity correlation by the P and the of observations in a correlation by the P and the of observations The study population consisted of men and women with FH The was of the participants were were and were The subjects were but blood of and HDL-C were The was higher than 8 which is for of the FH population = blood blood cholesterol familial high density LDL-C, low density are means for which the of and and which the of and in a familial high density LDL-C, low density are means for which the of and and which the of and the between the PON1 genotypes (L55M, Q192R, −107C/T, −162A/G, −824G/A, and −907G/C) and PON1 levels and All PON1 genotype were in The of the L55M polymorphism to increased PON1 levels (P < and increased paraoxonase, and arylesterase (P < P = and P = respectively). The of the Q192R polymorphism more whereas the more (P < for both The of and with the Q192R there was between the and the Q192R The Q192R polymorphism was not associated with PON1 levels with arylesterase between PON1 genotypes and PON1 levels and paraoxonase type means by the of observations P values are on in a paraoxonase type means by the of observations P values are on The and variants of the −107C/T, −162A/G, −824G/A, and polymorphisms in the promoter sequence higher PON1 levels, diazoxonase activity, and arylesterase activity than the and variants (P < for all arylesterase the has P = for and and P = for The hydrolysis rate of was higher for the and than for the genetic variants at and (P < and P = respectively). The of levels not the variants of these polymorphisms not the and polymorphisms were not associated with paraoxonase there was a correlation between PON1 levels and PON1 arylesterase = P < and PON1 diazoxonase = P < The contribution of PON1 genotypes to HDL-C levels is in The and variants of the L55M, Q192R, −107C/T, and polymorphisms increased HDL-C levels (P = 0.008, P = 0.020, P = 0.042, and P = respectively). After for and the relation between PON1 genotypes and HDL-C levels The and polymorphisms were not associated with HDL-C levels to PON1 means by the of observations P values are on P values are on and are for and in a means by the of observations P values are on P values are on and are for and the PON1 PON1 levels and paraoxonase, and arylesterase also to increased HDL-C levels = 0.37, P < 0.001; r = 0.23, P = r = 0.29, P = 0.001; and r = 0.19, P = we have an of PON1 genotypes and with plasma HDL we investigated the relation with circulating and with We no of PON1 genotypes with with Hs-CRP not in PON1 levels and activity also not with we only but of diazoxonase and arylesterase with Hs-CRP levels and Hs-CRP with to PON1 levels and levels activity activity activity C-reactive OxLDL, oxidized low density correlation by the P and the of observations in a C-reactive OxLDL, oxidized low density correlation by the P and the of observations we found of PON1 PON1 levels, and PON1 activity with HDL-C levels but not with circulating and We also investigated the relation of PON1 genotypes and with We found no relation between PON1 genotypes and CCA-IMT and no correlation of PON1 levels and PON1 with CCA-IMT OxLDL, and Hs-CRP not with to PON1 common carotid artery intima-media means by the of observations P values are on and for in a with to PON1 levels, PON1 OxLDL, and levels activity activity activity correlation by the P and the of observations in a common carotid artery intima-media means by the of observations P values are on and for correlation by the P and the of observations have that high PON1 levels and high PON1 activity contribute to increased levels of HDL-C Garin M.C. Abbott C. Messmer S. Mackness M. Durrington P. Pometta D. James R.W.W. Quantification of human serum paraoxonase by enzyme-linked immunoassay: population differences in protein concentrations.Biochem. J. 1994; 304: 549-554Crossref PubMed Scopus (116) Google Scholar, of serum paraoxonase polymorphism on serum and Genet. 1991; PubMed Scopus Google Scholar, M.C. James R.W. Messmer S. Pometta D. of a human high-density lipoprotein by a of with J. 1993; PubMed Scopus Google Scholar). The of the study and these by that not only high PON1 levels and high PON1 activity, but also the genotypes associated with high PON1 levels and and high PON1 activity were associated with the HDL-C These support the hypothesis that PON1 is in the preservation of HDL (4Aviram M. Rosenblat M. Bisgaier C.L. Newton R.S. Primo-Parmo S.L. La Du B.N.N. Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase.J. Clin. 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S. of between carotid intima-media thickness and paraoxonase gene polymorphism in 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), the of of PON1 with not the of its in the of the Therefore, we that on PON1 be in with the function of PON1 may influence inhibition of LDL oxidation M.I. Arrol S. Durrington P.N. Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein.FEBS Lett. 1991; 286: 152-154Crossref PubMed Scopus Google Scholar, M.I. Arrol S. Abbott C. Durrington P.N. of low-density lipoprotein against oxidative modification by high-density lipoprotein associated 1993; Full Text PDF PubMed Scopus Google Scholar, Hama La Du Fogelman A.M. Navab of high density lipoprotein associated of the activity of oxidized low density Clin. Invest. PubMed Scopus Google Scholar), in that cholesterol by and 2000; PubMed Scopus Google Scholar). inhibition of LDL oxidation may inflammation in the arterial wall R. J. 1999; PubMed Scopus Google Scholar). 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We studied the relation between PON1 and circulating as a marker for LDL oxidation and Hs-CRP as a marker for inflammation and could not that PON1 is in the of the inhibition of LDL oxidation and the of is because the of PON1 on circulating and Hs-CRP to be in on the role of PON1 and CVD are to PON1 However, additional measurements of PON1 serum levels and a more complete view of PON1 because the genetic and effects of In the study, PON1 was determined using genotypes (L55M, Q192R, −107C/T, −162A/G, −824G/A, and PON1 levels, and activity diazoxon, and phenyl The PON1 genotypes were determined in all but PON1 serum and activity measurements were to 134 of the 302 the was to a relation between PON1 genotypes and PON1 levels and The between the coding and promoter polymorphisms and PON1 levels and activity are in with the and to the PON1 levels (7Garin M.C. James R.W. Dussoix P. Blanche H. Passa P. Froguel P. Ruiz J.J. Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes.J. Clin. Invest. 1997; 99: 62-66Crossref PubMed Google Scholar, I. James R.W. polymorphisms of human paraoxonase PON1 gene and serum paraoxonase and Thromb. Vasc. Biol. 2000; PubMed Scopus Google Scholar, V.H. McKinstry L.A. G.P. Furlong C.E.E. of polymorphisms on (PON1) J. Hum. Genet. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). as described in the the Q192R polymorphism was for the in the hydrolysis and but not phenyl Richter R.J. M. J. Furlong C.E.E. The of the human serum paraoxonase polymorphism is with diazoxon, and Genet. PubMed Scopus Google Scholar). the activity measurements and the Q192R were because there was between PON1 and the between the hydrolysis rate of and and Q192R genotyping. However, the physiological of PON1 is and measurements of PON1 activity by the of hydrolysis of phenyl paraoxon, and may not the of antiatherogenic of PON1 and be as surrogate markers of PON1 In this study, PON1 levels and PON1 were measured at was a correlation the PON1 levels with and the PON1 activity Therefore, PON1 activity measurements as surrogate markers for PON1 levels in We that the of effects of PON1 on CVD increased in a population at high risk for atherosclerosis and CVD. For this reason, we investigated the effects of PON1 in a population of patients with FH. These patients have increased lipid levels and a lipid that is that of the population at such a population may not be to the general population. In PON1 is in the preservation of HDL-C in plasma and therefore may protect against CVD. The genetic variants associated with high PON1 levels and activity and the high plasma levels and increased activity of PON1 the levels of PON1 HDL-C was associated with are to the of the activity of PON1 in with This study was supported by the The and for their